Pathological conditions resulting in tissue degradation such as cartilage degradation constitute a major medical, social and economical problem. Of persons older than 65 years of age, about 50% of the population in the Western world has arthritis. Tissue degradation processes are characterized by destruction of tissues by the breakdown of its components. The tissue components can be degraded due to enzymes, often proteases, or by toxic compounds. For this reason, determination of tissue degradation processes for the purpose of diagnosis, disease monitoring, treatment etc. can be performed by numerous methods. One way to determine degradation processes in connective tissue diseases, such as arthritic conditions, arteriosclerosis, degenerative joint conditions etc., is the detection of formation and presence of degradation products of the connective tissue components. This allows direct detection of the degradation process, compared to indirect methods as e.g. loss of tissue, inflammation, swelling and presence of autoreactive autoantibodies, which have been widely employed in the diagnosis of joint disease, such as arthritic conditions.
Traditionally, the clinical diagnosis of arthritis is based on the patient's history, physical examination, radiographs and measures of inflammation inducing autoantibodies. The prognosis, treatment and clinical outcome of patients with arthritis are assessed by serial determinations. However, in order to minimize permanent tissue damage caused by pathological conditions involving cartilage degeneration, it is important to be able to diagnose such conditions at an early stage. Accordingly, during the last decade efforts have been made to find suitable biological markers that enable an early detection of pathological cartilage degeneration.
Elevated serum levels of COMP have previously been associated with ongoing joint destruction in rheumatoid arthritis (Månsson et al, J. Clin. Invest (1995), vol. 95, pp 1077-1077; Wollheim et al., British Journal of Rheumatology (1997), vol. 36, pp 847-849; Petersson et al., British Journal of Rheumatology (1998), vol. 37, pp 46-50). Significant amounts of fragments of COMP have also been found in synovial fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis (Neidhardt et al., British Journal of Rheumatology (1997), vol. 36, pp 1151-1160).
It has also been suggested to use COMP or nucleic acid sequences encoding COMP for preparing a pharmaceutical composition for preventing and/or treating arthritic conditions in a mammal (WO 98/46253). Accordingly, COMP can be regarded as a key compound when diagnosing and/or treating different forms of arthritis.
COMP has previously been used as a marker of cartilage turnover (Saxne et al., British Journal of Rheumatology (1992), vol. 31, pp. 583-591). Lai et al., (Osteoarthritis Cartilage (2012), vol. 20, pp 854-862) developed a sandwich ELISA where serum COMP fragments are used for monitoring the arthritic progression. They show difference in serum COMP levels between arthritic patients and non-arthritic control subjects.
A method for determining a tissue degradation process by detection of neoepitopes is disclosed in WO 2005/116658, where neoepitopes that appear after cleavage of COMP between 625 and 626 of the amino acid sequence of COMP are used.
In Söderlin M. (2003) A population-based study on early arthritis in southern Sweden. Incidence, preceding infections, diagnostic markers and economic burden. Doctoral dissertation, Linköping University, Department of Molecular and Clinical Medicine COMP is used as a marker, but could not show any statistical difference between different diagnosis groups and even in the control group 18% of the patients had elevated COMP levels.
The results of the methods used today, for diagnosis and monitoring of diseases such as for example arthritis, show a great overlap between disease and non-disease patients as a result of high background from normal tissue turnover.
A major limitation with the prior methods and techniques is that they are not able to distinguish between pathological cartilage turnover from normal turnover, due to high background levels from normal cartilage turnover. Hence, there are still room for improvements within the technical field.